Hormone Therapy Compared With Combination Chemotherapy in Treating Patients With Prostate Cancer

OBJECTIVES:

• Compare time to objective progression in patients with prostate cancer and a rising prostate-specific antigen (PSA) after androgen suppression when treated with second-line hormonal therapy (ketoconazole and hydrocortisone) vs combination chemotherapy (docetaxel and estramustine).
• Compare time to PSA progression and correlate this with time to objective progression in patients treated with these regimens.
• Compare the quality of life in patients treated with these regimens.
• Compare overall survival of patients treated with these regimens.
• Compare the natural history of progression in patients treated with these regimens.
• Identify prognostic indicators of clinical outcome by immunohistochemical evaluation of apoptopic biomarkers in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior treatment with bisphosphonates (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral ketoconazole three times daily and oral hydrocortisone twice daily. Treatment continues in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral estramustine three times daily on days 1-5 and docetaxel IV over 1 hour on day 2. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, on day 1 of week 9, at 6 months and 1 year, and then annually for up to 10 years or until beginning of first non-protocol therapy.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 590 patients (295 per treatment arm) will be accrued for this study within 4 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate that was continuously treated with androgen suppression
• Rising prostate-specific antigen (PSA), defined as PSA > 5 ng/mL, rising on 2 consecutive measurements at least 4 weeks apart
• Gleason score 7 or higher and/or seminal vesicle involvement at diagnosis
• Patients previously treated with antiandrogen or glucocorticoid therapy must meet the following criteria:

• Must show a continued rise in PSA after stopping antiandrogen (flutamide, bicalutamide, or nilutamide) or glucocorticoid (dexamethasone or prednisone)

• At least 4 weeks continued rise in PSA after flutamide or nilutamide (6 weeks for bicalutamide)
• Testosterone less than 50 ng/dL

• Patients who have not undergone surgical castration must continue primary androgen suppression to maintain castrate levels of testosterone
• No progressive or measurable local or metastatic disease (including bone metastases)

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Granulocyte count at least 2,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• SGOT no greater than 2 times upper limit of normal
• Bilirubin no greater than 1.5 mg/dL

Renal:

• Creatinine no greater than 1.7 mg/dL

Cardiovascular:

• No American Heart Association class III or IV heart disease
• No uncontrolled congestive heart failure
• No life-threatening cardiac arrhythmias

Other:

• Fertile patients must use effective contraception
• No other prior malignancy unless curatively treated and disease-free for appropriate time period for specific cancer
• No preexisting peripheral neuropathy greater than grade 1
• No known hypersensitivity to polysorbate 80

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• At least 5 years since prior systemic chemotherapy

Endocrine therapy:

• See Disease Characteristics
• At least 4 weeks since prior hydrocortisone
• No prior ketoconazole

Radiotherapy:

• At least 28 days since prior radiotherapy to primary site
• No prior palliative radiotherapy
• No concurrent radiotherapy

Surgery:

• See Disease Characteristics

Other:

• Recovered form prior therapy
• At least 7 days since prior parenteral antibiotics for active infection
• No concurrent digitalis
• No concurrent H_2 blockers or proton pump inhibitors (arm I only)
• Concurrent bisphosphonates allowed provided they were initiated prior to study therapy